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Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation.

Kiselyov VV, Versteyhe S, Gauguin L, De Meyts P - Mol. Syst. Biol. (2009)

Bottom Line: On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator.Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters.The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs.

View Article: PubMed Central - PubMed

Affiliation: Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark. vkis@novonordisk.com

ABSTRACT
The insulin and insulin-like growth factor 1 receptors activate overlapping signalling pathways that are critical for growth, metabolism, survival and longevity. Their mechanism of ligand binding and activation displays complex allosteric properties, which no mathematical model has been able to account for. Modelling these receptors' binding and activation in terms of interactions between the molecular components is problematical due to many unknown biochemical and structural details. Moreover, substantial combinatorial complexity originating from multivalent ligand binding further complicates the problem. On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator. Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters. The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs.

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Inactive (A) and crosslinked (B, C) insulin receptor intermediaries used in the model. S1 and S2 stand for sites 1 and 2, respectively. Insulin is depicted as a black dot.
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f2: Inactive (A) and crosslinked (B, C) insulin receptor intermediaries used in the model. S1 and S2 stand for sites 1 and 2, respectively. Insulin is depicted as a black dot.

Mentions: The structure of the insulin receptor dimer in the unliganded conformation displays a symmetrical antiparallel arrangement of the receptor's two binding sites for insulin (McKern et al, 2006) (see Figure 1A and C). From now on, a pair of sites 1 and 2 from the different receptor subunits will be referred to as a ‘crosslink'. The structure shows that the distance between sites 1 and 2 (within the same crosslink) is rather small (see Figure 1B), indicating that if an insulin molecule binds to either of these sites, there is not enough room for binding of a second insulin molecule. Thus, it is reasonable to assume that only one insulin molecule can bind to the same crosslink (either to site 1 or 2), when the receptor dimer is in the inactive conformation. Mathematical modelling of insulin binding to the inactive conformation of the insulin receptor is straightforward and requires only four parameters: association rate constants for sites 1 and 2 (designated a1 and a2, respectively) and dissociation rate constants for sites 1 and 2 (designated d1 and d2, respectively). The four sites will from now on be designated as sites 1, 2, 3 and 4, where sites 3 and 4 are identical to sites 1 and 2, respectively, but from a different crosslink (see Figure 2A). Binding of insulin to the inactive conformation of the insulin receptor gives rise to nine intermediaries, designated r0, r1, r2, r3, r4, r13, r14, r23 and r24 (where indices i and j in ri and rij designate the number of the site to which insulin is bound) (see Figure 2A).


Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation.

Kiselyov VV, Versteyhe S, Gauguin L, De Meyts P - Mol. Syst. Biol. (2009)

Inactive (A) and crosslinked (B, C) insulin receptor intermediaries used in the model. S1 and S2 stand for sites 1 and 2, respectively. Insulin is depicted as a black dot.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2657531&req=5

f2: Inactive (A) and crosslinked (B, C) insulin receptor intermediaries used in the model. S1 and S2 stand for sites 1 and 2, respectively. Insulin is depicted as a black dot.
Mentions: The structure of the insulin receptor dimer in the unliganded conformation displays a symmetrical antiparallel arrangement of the receptor's two binding sites for insulin (McKern et al, 2006) (see Figure 1A and C). From now on, a pair of sites 1 and 2 from the different receptor subunits will be referred to as a ‘crosslink'. The structure shows that the distance between sites 1 and 2 (within the same crosslink) is rather small (see Figure 1B), indicating that if an insulin molecule binds to either of these sites, there is not enough room for binding of a second insulin molecule. Thus, it is reasonable to assume that only one insulin molecule can bind to the same crosslink (either to site 1 or 2), when the receptor dimer is in the inactive conformation. Mathematical modelling of insulin binding to the inactive conformation of the insulin receptor is straightforward and requires only four parameters: association rate constants for sites 1 and 2 (designated a1 and a2, respectively) and dissociation rate constants for sites 1 and 2 (designated d1 and d2, respectively). The four sites will from now on be designated as sites 1, 2, 3 and 4, where sites 3 and 4 are identical to sites 1 and 2, respectively, but from a different crosslink (see Figure 2A). Binding of insulin to the inactive conformation of the insulin receptor gives rise to nine intermediaries, designated r0, r1, r2, r3, r4, r13, r14, r23 and r24 (where indices i and j in ri and rij designate the number of the site to which insulin is bound) (see Figure 2A).

Bottom Line: On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator.Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters.The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs.

View Article: PubMed Central - PubMed

Affiliation: Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark. vkis@novonordisk.com

ABSTRACT
The insulin and insulin-like growth factor 1 receptors activate overlapping signalling pathways that are critical for growth, metabolism, survival and longevity. Their mechanism of ligand binding and activation displays complex allosteric properties, which no mathematical model has been able to account for. Modelling these receptors' binding and activation in terms of interactions between the molecular components is problematical due to many unknown biochemical and structural details. Moreover, substantial combinatorial complexity originating from multivalent ligand binding further complicates the problem. On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator. Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters. The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs.

Show MeSH